Stretchable ionic-electronic bilayer hydrogel electronics enable in situ detection of solid-state epidermal biomarkers.

Continuous and in situ detection of biomarkers in biofluids (for example, sweat) can provide critical health data but is limited by biofluid accessibility. Here we report a sensor design that enables in situ detection of solid-state biomarkers ubiquitously present on human skin. We deploy an ionic-electronic bilayer hydrogel to facilitate the sequential dissolution, diffusion and electrochemical reaction of solid-state analytes. We demonstrate continuous monitoring of water-soluble analytes (for example, solid lactate) and water-insoluble analytes (for example, solid cholesterol) with ultralow detection limits of 0.51 and 0.26 nmol cm-2, respectively. Additionally, the bilayer hydrogel electrochemical interface reduces motion artefacts by a factor of three compared with conventional liquid-sensing electrochemical interfaces. In a clinical study, solid-state epidermal biomarkers measured by our stretchable wearable sensors showed a high correlation with biomarkers in human blood and dynamically correlated with physiological activities. These results present routes to universal platforms for biomarker monitoring without the need for biofluid acquisition.

Radiation therapy with phenotypic medicine: towards N-of-1 personalization.

In current clinical practice, radiotherapy (RT) is prescribed as a pre-determined total dose divided over daily doses (fractions) given over several weeks. The treatment response is typically assessed months after the end of RT. However, the conventional one-dose-fits-all strategy may not achieve the desired outcome, owing to patient and tumor heterogeneity. Therefore, a treatment strategy that allows for RT dose personalization based on each individual response is preferred. Multiple strategies have been adopted to address this challenge. As an alternative to current known strategies, artificial intelligence (AI)-derived mechanism-independent small data phenotypic medicine (PM) platforms may be utilized for N-of-1 RT personalization. Unlike existing big data approaches, PM does not engage in model refining, training, and validation, and guides treatment by utilizing prospectively collected patient's own small datasets. With PM, clinicians may guide patients' RT dose recommendations using their responses in real-time and potentially avoid over-treatment in good responders and under-treatment in poor responders. In this paper, we discuss the potential of engaging PM to guide clinicians on upfront dose selections and ongoing adaptations during RT, as well as considerations and limitations for implementation. For practicing oncologists, clinical trialists, and researchers, PM can either be implemented as a standalone strategy or in complement with other existing RT personalizations. In addition, PM can either be used for monotherapeutic RT personalization, or in combination with other therapeutics (e.g. chemotherapy, targeted therapy). The potential of N-of-1 RT personalization with drugs will also be presented.

National expert consensus on short-acting beta2-agonist overreliance in asthma care in Malaysia.

OBJECTIVE: Inappropriate use of short-acting beta2-agonists (SABA) in asthma has been associated with undesired outcomes. This national expert consensus was developed to increase awareness of SABA overuse and provide recommendations on the ways to eliminate SABA overprescription and overreliance in Malaysia. DATA SOURCES: This expert consensus was developed by searching the PubMed database, using index terms to identify SABA overuse-related burden and recommendations made in asthma guidelines. Consensus recommendations were made via the Delphi method, involving a Malaysian expert committee comprising 13 healthcare professionals (five pulmonologists, four family medicine specialists, two emergency medicine physicians and two pharmacists). STUDY SELECTIONS: The articles reviewed include randomized controlled trials, systematic reviews, meta-analyses, observational studies, guidelines, and surveys, with abstracts in English and published up until June 2023. Relevant recommendations were also sourced from verified websites of medical organizations and societies. RESULTS: Eleven consensus statements were developed, each statement achieving a priori agreement level of at least 70%. The statements reflect SABA overreliance in asthma care, as well as recommendations to eliminate SABA overprescription and overreliance in Malaysia. Supporting evidence in the literature as well as expert committee discussions leading to the development of the finalized statements were elaborated. CONCLUSION: This national expert consensus discussed the burden of SABA overreliance and made specific recommendations to eliminate SABA overprescription and overreliance in the Malaysian context. This consensus document is anticipated to impart better awareness among Malaysian healthcare providers and contribute to the continuous improvement of asthma care in the country.

Photoreceptor laminin drives differentiation of human pluripotent stem cells to photoreceptor progenitors that partially restore retina function.

Blindness caused by advanced stages of inherited retinal diseases and age-related macular degeneration are characterized by photoreceptor loss. Cell therapy involving replacement with functional photoreceptor-like cells generated from human pluripotent stem cells holds great promise. Here, we generated a human recombinant retina-specific laminin isoform, LN523, and demonstrated the role in promoting the differentiation of human embryonic stem cells into photoreceptor progenitors. This chemically defined and xenogen-free method enables reproducible production of photoreceptor progenitors within 32 days. We observed that the transplantation into rd10 mice were able to protect the host photoreceptor outer nuclear layer (ONL) up to 2 weeks post transplantation as measured by full-field electroretinogram. At 4 weeks post transplantation, the engrafted cells were found to survive, mature, and associate with the host's rod bipolar cells. Visual behavioral assessment using the water maze swimming test demonstrated visual improvement in the cell-transplanted rodents. At 20 weeks post transplantation, the maturing engrafted cells were able to replace the loss of host ONL by extensive association with host bipolar cells and synapses. Post-transplanted rabbit model also provided congruent evidence for synaptic connectivity with the degenerated host retina. The results may pave the way for the development of stem cell-based therapeutics for retina degeneration.

Unique dynamics and exocytosis properties of GABAergic synaptic vesicles revealed by three-dimensional single vesicle tracking.

Maintaining the balance between neuronal excitation and inhibition is essential for proper function of the central nervous system. Inhibitory synaptic transmission plays an important role in maintaining this balance. Although inhibitory transmission has higher kinetic demands compared to excitatory transmission, its properties are poorly understood. In particular, the dynamics and exocytosis of single inhibitory vesicles have not been investigated, due largely to both technical and practical limitations. Using a combination of quantum dots (QDs) conjugated to antibodies against the luminal domain of the vesicular GABA transporter to selectively label GABAergic (i.e., predominantly inhibitory) vesicles together with dual-focus imaging optics, we tracked the real-time three-dimensional position of single GABAergic vesicles up to the moment of exocytosis (i.e., fusion). Using three-dimensional trajectories, we found that GABAergic synaptic vesicles traveled a shorter distance prior to fusion and had a shorter time to fusion compared to synaptotagmin-1 (Syt1)-labeled vesicles, which were mostly from excitatory neurons. Moreover, our analysis revealed that GABAergic synaptic vesicles move more straightly to their release sites than Syt1-labeled vesicles. Finally, we found that GABAergic vesicles have a higher prevalence of kiss-and-run fusion than Syt1-labeled vesicles. These results indicate that inhibitory synaptic vesicles have a unique set of dynamics and exocytosis properties to support rapid synaptic inhibition, thereby maintaining a tightly regulated coordination between excitation and inhibition in the central nervous system.

Comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for low-risk gestational trophoblastic neoplasia (FIGO Score 0-4): study protocol for a prospective, multicentre, randomized trial.

BACKGROUND: Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens. METHODS: We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m2) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life. DISCUSSION: Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0).

Fatty acid profile, minor bioactive constituents and physicochemical properties of insect-based oils: A comprehensive review.

Insect-based food or ingredients have received tremendous attention worldwide because of their potential to ensure food and nutrition security, mitigating the reliance on land-dependent agricultural products. Indeed, insect-farming has low environmental impacts with reduced land, water and energy input. More importantly, insects are rich in high quality proteins and fats. They are also excellent sources of minerals, vitamins and bioactive compounds. Insect-based lipids are intriguing because they may contain high levels of unsaturated fatty acids particularly linoleic and α-linolenic acids. Besides, the insect-based lipids also show a considerable amount of bioactive components such as tocols, sterols and carotenoids. However, their fatty acid compositions and the nutritional values may vary depending on species, feed composition, developmental stage, geographical locations, and extraction techniques. Therefore, the present article aims to provide a comprehensive review on the fatty acid composition, the minor bioactive constituents and the physicochemical properties of fats and oils derived from insects of different orders (Coleoptera, Lepidoptera, Hymenoptera, Orthoptera, Hemiptera and Diptera). The various parameters affecting the nutritional compositions of the insect-based lipids will also be highlighted. These information will definitely provide a detailed insight on the potential applications of these fats in various food systems based on their unique properties.

Integration of genome-wide association studies (GWAS) and microbiome data highlights the impact of sulfate-reducing bacteria on Alzheimer's disease.

BACKGROUND: observational studies have indicated that gut microbiome dysbiosis was associated with Alzheimer's disease (ad). However, the results are largely inconsistent and it remains unknown whether the association is causal in nature. METHODS: leveraging observational studies and genome-wide association studies (GWAS) on the gut microbiome in ad patients, we pooled the microbiome data (N = 1,109) to screen the microbiota significantly altered in ad patients and then conducted Mendelian randomisation (MR) study to determine the causal associations between altered microbiota (N = 18,340) and ad using two different ad GWAS datasets (N = 63,926 and N = 472,868) using the inverse variance-weighted (IVW) method. RESULTS: the combined effect sizes from observational studies showed that 8 phyla, 18 classes, 22 orders, 37 families, 78 genera and 109 species significantly changed in ad patients. Using the MR analysis, we found that two classes, one order, one family and one genus were suggestively associated with ad consistently in two different GWAS datasets. Both observational studies and MR analysis simultaneously showed that Desulfovibrionales (order) and Desulfovibrionaceae (family), which were mainly implicated in dissimilatory sulfate reduction, were significantly associated with an elevated risk of ad. CONCLUSIONS: our findings demonstrated that the abundance of sulfate-reducing bacteria was increased in ad patients, which was causally linked to an increased risk of ad. Further efforts are warranted to clarify the underlying mechanisms, which will provide new insight into the prevention and treatment of ad.

Genomic analysis and biological characterization of a novel Schitoviridae phage infecting Vibrio alginolyticus.

Vibrio alginolyticus is a Gram-negative bacterium commonly associated with mackerel poisoning. A bacteriophage that specifically targets and lyses this bacterium could be employed as a biocontrol agent for treating the bacterial infection or improving the shelf-life of mackerel products. However, only a few well-characterized V. alginolyticus phages have been reported in the literature. In this study, a novel lytic phage, named ΦImVa-1, specifically infecting V. alginolyticus strain ATCC 17749, was isolated from Indian mackerel. The phage has a short latent period of 15 min and a burst size of approximately 66 particles per infected bacterium. ΦImVa-1 remained stable for 2 h at a wide temperature (27-75 °C) and within a pH range of 5 to 10. Transmission electron microscopy revealed that ΦImVa-1 has an icosahedral head of approximately 60 nm in diameter with a short tail, resembling those in the Schitoviridae family. High throughput sequencing and bioinformatics analysis elucidated that ΦImVa-1 has a linear dsDNA genome of 77,479 base pairs (bp), with a G + C content of ~ 38.72% and 110 predicted gene coding regions (106 open reading frames and four tRNAs). The genome contains an extremely large virion-associated RNA polymerase gene and two smaller non-virion-associated RNA polymerase genes, which are hallmarks of schitoviruses. No antibiotic genes were found in the ΦImVa-1 genome. This is the first paper describing the biological properties, morphology, and the complete genome of a V. alginolyticus-infecting schitovirus. When raw mackerel fish flesh slices were treated with ΦImVa-1, the pathogen loads reduced significantly, demonstrating the potential of the phage as a biocontrol agent for V. alginolyticus strain ATCC 17749 in the food. KEY POINTS: • A novel schitovirus infecting Vibrio alginolyticus ATCC 17749 was isolated from Indian mackerel. • The complete genome of the phage was determined, analyzed, and compared with other phages. • The phage is heat stable making it a potential biocontrol agent in extreme environments.

Protein-Templated Metal Nanoclusters: Molecular-like Hybrids for Biosensing, Diagnostics and Pharmaceutics.

The use of proteins as biomolecular templates to synthesize atomically precise metal nanoclusters has been gaining traction due to their appealing properties such as photoluminescence, good colloidal- and photostability and biocompatibility. The synergistic effect of using a protein scaffold and metal nanoclusters makes it especially attractive for biomedical applications. Unlike other reviews, we focus on proteins in general as the protective ligand for various metal nanoclusters and highlight their applications in the biomedical field. We first introduce the approaches and underlined principles in synthesizing protein-templated metal nanoclusters and summarize some of the typical proteins that have been used thus far. Afterwards, we highlight the key physicochemical properties and the characterization techniques commonly used for the size, structure and optical properties of protein-templated metal nanoclusters. We feature two case studies to illustrate the importance of combining these characterization techniques to elucidate the formation process of protein-templated metal nanoclusters. Lastly, we highlight the promising applications of protein-templated metal nanoclusters in three areas-biosensing, diagnostics and therapeutics.

The effect of work setting and demographic factors on caring behaviour among nurses in the public hospitals and public health services, Sabah, Malaysia.

BACKGROUND: The nursing profession's uniqueness contributes to the development of knowledge, experience, age, education, economy, and position, as well as a unique gender role. Thus, the development and advancement of demographic characteristics of nurses while in this profession influences their caring behavior. OBJECTIVE: The purpose of this study was to determine the effect of work setting and demographic factors on nurses' caring behaviour, as well as the differences in nurses' caring behaviour based on demographic factors between nurses in public hospitals and nurses in public health services in Sabah, Malaysia. METHODS: This research is a cross-sectional study using the survey method. Data were collected from 3,532 nurses (88.3% response rate) in public hospitals and public health services within Sabah, Malaysia. Data were analysed using two-way ANOVA. RESULTS: The two-way ANOVA test revealed no significant impact of the work setting on CB, nor was there a notable interaction between the work setting and demographic factors influencing nurses' CB. However, demographic factors such as gender, age, education, economic status, position, and experience had a significant effect on CB. CONCLUSION: The present research has provided convergent evidence on the effect of demographic factors on nurses caring behavior and the differences in caring behavior based on demographic factors among nurses in public hospitals and public health services in Sabah, Malaysia.

Effect of primary and secondary Fasciola gigantica infection on specific IgG responses, hepatic enzyme levels and weight gain in buffaloes.

Buffaloes, as highly susceptible definitive hosts of Fasciola gigantica, suffer from a high infection rate of fasciolosis, which causes enormous economic losses. Repeat infection is responsible for this high rate; thus, elucidating the protective immunity mechanism in repeat infection is decisive in fasciolosis prevention. Herein, a secondary experimental infection model was established to preliminarily reveal the protective immunity that occurs in repeat infection. In brief, animals were assigned to three groups: group A (uninfected control), group B (primary infection) and group C (secondary infection). Buffaloes were autopsied 20 weeks post-infection for measurements of the recovered flukes and hepatic examination. In addition, the detection of specific antibody (IgG) responses to F. gigantica excretory-secretory product (FgESP) throughout the whole period and weight gain throughout the first 4 months as a percentage (%) of the starting weight were also determined. The serum hepatic enzyme gamma glutathione transferase (GGT) levels were monitored to assess hepatic damage throughout the study period. Infection establishment was compared between group B and group C. Similar specific IgG patterns were observed between group B and group C, and hepatic damage was more severe in group C than group B. Significant differences in weight gain as a percentage of the start weight were observed between group A and group B at the 3rd and 4th months postprimary infection, while significant differences were not observed between group A and group C or group B and group C. Our results suggest that challenge infection cannot induce resistance against F. gigantica in buffaloes, which is consistent with the protective immunity against Fasciola hepatica reinfection observed in sheep and goats.

Comparative study of umbilical cord cross-sectional area in foetuses with isolated single umbilical artery and normal umbilical artery.

Single umbilical artery (SUA) is one of the most common prenatal diagnoses in cases of foetal abnormality. This prospective study evaluated 77 foetuses with isolated SUAs and 77 healthy foetuses, both at 22-39 gestational weeks. We categorised gestational age into the second and third trimesters, measured the umbilical arterial blood flow parameters and calculated the umbilical vein (UV) area, umbilical artery (UA) area and UV area/UA area ratio. In the second and third trimesters, a higher UA area was obtained in the isolated SUA group than in the control group (p < .01). Furthermore, the isolated SUA group had a lower UV area/UA area ratio than the control group (p < .01), and a positive linear correlation was found between gestational age and UV area in both groups (p < .01). The presence of isolated SUAs was associated with low birth weight and a high prevalence of small for gestational age.IMPACT STATEMENTWhat is already known on this subject? Single umbilical artery (SUA) is one of the most common prenatally diagnosed foetal abnormalities and approximately 80% foetuses with SUA have isolated SUA, which is a soft indicator of chromosome abnormalities, congenital malformations and premature birth. Umbilical cord cross-sectional area can be evaluated prenatally by ultrasound imaging. Normal values increase with gestational age and foetal size in single pregnancies. Changes in umbilical cord thickness have been associated with complications during pregnancy.What do the results of this study add? The correlation between gestational age and umbilical vein area in the isolated single umbilical artery (SUA) group and control group was better than that between gestational age and umbilical artery area. UA area increased significantly in both groups before 28 weeks but not after 28 weeks, particularly in the isolated SUA group.What are the implications of these findings for clinical practice and/or further research? The study provides a reliable basis for maternal foetal monitoring during pregnancy in the isolated SUA and control groups. Objective assessment of the occurrence and development of foetuses with isolated single umbilical artery was performed.

[Quality standard and quality value transfer of reference samples of classical prescription Huagan Decoction].

The detection method of characteristic spectrum for reference samples was established by preparing 15 batches of the reference samples of Huagan Decoction, and the peak attribution and the similarity range in the characteristic spectrum were clarified. The ranges of paste-forming rate, content, and transfer rate of the index components including geniposide, paeonol, and paeoniflorin were analyzed. The key quality attribute of the reference samples of Huagan Decoction was defined. The results showed that the 15 batches of the reference samples of Huagan Decoction had good similarities in the characteristic spectrum, which were all higher than 0.9. According to the information of characteristic peak, there were 18 characteristic peaks in the whole prescription, including seven common characteristic peaks from green tangerine peel and dried tangerine peel, four characteristic peaks from tree peony root bark(three of them were common characteristic peaks from tree peony root bark and red peony root), five characteristic peaks from cape jasmine fruit, one characteristic peak from paniculate bolbostemma, and one characteristic peak from oriental waterplantain rhizome.The paste-forming rate of the 15 batches of reference samples was 14.73%-18.83%. The content of geniposide was 1.68%-2.87%, with the average transfer rate of 70.05%±11.13%. The content of paeonol was 0.10%-0.16%, with the average transfer rate of 9.38%±1.78%. The content of paeoniflorin was 1.94%-2.74%, with the average transfer rate of 36.69%±4.63%. This study analyzed the quality value transfer of the reference samples of Huagan Decoction by the evaluation mode of combining the characteristic spectrum, the paste-forming rate, and the content of index components. The findings of this study initially established a stable and feasible standard decoction evaluation method and provided references for the quality control and the subsequent development of relevant preparations of Huagan Decoction.

Changing Paradigm for Vertigo/Dizziness Patients: a Retrospective Before-After Study from Tertiary Hospitals in Northwestern China.

BACKGROUND: Single disciplinary management of patients with vertigo and dizziness is an important challenge for most physicians in China. OBJECTIVE: To assess the impact of a new paradigm of practice (Clinic for Vertigo and Dizziness, CVD) performed by a multidisciplinary team (MDT) on diagnostic spectrum, medical costs, and patient satisfaction. DESIGN: Retrospective before-after study. PARTICIPANTS: Sample of 29,793 patients with vertigo/dizziness as primary complaint. MEASURES: Changes in diagnostic spectrum, medical costs, and patient satisfaction before and after the establishment of a CVD based on a 4-year database in three tertiary hospitals in northwestern China. KEY RESULTS: The most common diagnoses of patients with vertigo and dizziness were Meniere's disease (25.77%), cervical disease (25.00%), cerebral vascular disease (13.96%), vestibular syndrome (10.57%), and other etiologies (6.34%) before the CVD establishment. In contrast, after the CVD establishment, the most common diagnoses were BPPV (23.92%), vestibular migraine (15.83%), Meniere's disease (14.22%), CSD/PPPD (11.61%), and cerebral vascular diseases (4.45%). Extended implementation of a structured questionnaire for vertigo/dizziness and vestibular-oriented examinations (nystagmus, positional tests, HINTS) at the CVD resulted in a remarkable decline in the utility of CT/MRI and X-ray examination (p < 0.001). Meanwhile, medical costs in patients with vertigo/dizziness dropped by 11.5% (p < 0.001), with a significant improvement in patient satisfaction after the establishment of CVD (p < 0.001). CONCLUSIONS AND RELEVANCE: Our study suggested that the MDT paradigm of CVD practice may facilitate the medical management of patients with vertigo/dizziness and improve patient satisfaction.

Prenatal sonographic diagnosis of X-linked hypohidrotic ectodermal dysplasia: An unusual case.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare congenital genetic disorder caused by mutations in the ectodysplasin A gene, resulting in dysplasia or complete absence of teeth, hair, and sweat glands. XLHED is rarely diagnosed prenatally. We describe a case of XLHED diagnosed with prenatal sonography and umbilical cord blood gene testing.

Drug Discovery of Spinal Muscular Atrophy (SMA) from the Computational Perspective: A Comprehensive Review.

Spinal muscular atrophy (SMA), one of the leading inherited causes of child mortality, is a rare neuromuscular disease arising from loss-of-function mutations of the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein. When lacking the SMN protein in neurons, patients suffer from muscle weakness and atrophy, and in the severe cases, respiratory failure and death. Several therapeutic approaches show promise with human testing and three medications have been approved by the U.S. Food and Drug Administration (FDA) to date. Despite the shown promise of these approved therapies, there are some crucial limitations, one of the most important being the cost. The FDA-approved drugs are high-priced and are shortlisted among the most expensive treatments in the world. The price is still far beyond affordable and may serve as a burden for patients. The blooming of the biomedical data and advancement of computational approaches have opened new possibilities for SMA therapeutic development. This article highlights the present status of computationally aided approaches, including in silico drug repurposing, network driven drug discovery as well as artificial intelligence (AI)-assisted drug discovery, and discusses the future prospects.

Transcendental meditation and hypothalamic-pituitary-adrenal axis functioning: a pilot, randomized controlled trial with young adults.

Transcendental meditation (TM) is effective in alleviating stress and anxiety and promoting well-being. While the underlying biological mechanisms of TM are not yet fully explored, the hypothalamic-pituitary-adrenal (HPA) axis represents an index providing important clues embodying the stress system cascade. In this pilot study, young adults were randomly assigned to TM training followed by 8 weeks of meditation practice or a wait-list control condition. TM was conducted over 8 weeks. Thirty-four young adult participants were randomized; 27 participants completed the HPA outcome assessments (41% male). To assess HPA axis functioning, salivary samples to assess cortisol awakening response (CAR) that were collected in the morning, both at baseline and at week-4. Salivary cortisol in the context of a social stressor using the Trier Social Stress Test (TSST) was collected at week-8. The results indicate that participants who were randomly assigned to TM had lower awakening salivary cortisol levels and a greater drop in CAR from baseline to week-4 than the control group. There were no significant differences in HPA axis functioning in the context of the TSST. Primary limitations of this randomized controlled trial were the small sample size, the use of a wait-list as opposed to an active control, and the limited scope of HPA axis assessments. The results of this pilot study provide tentative evidence that TM may impact biological stress system functioning and suggests that this may be a worthwhile avenue to continue to examine. It will also be useful to extend these findings to a broader array of meditative and mindful practices, particularly for those who are experiencing more distress.

Structural evolution of in situ boron-doped SiGe ultrathin film analyzed by multi-optical methods.

In situ boron (B)-doped SiGe (BSG) layer is extensively used in the source (S)/(D) drain of metal-oxide-semiconductor field-effect transistors. An unexpected structural evolution occurs in BSG during metallization and activation annealing during actual fabrication, which involves a correlated interaction between B and SiGe. Herein, the complicated phenomena of the structural evolution of BSG were analyzed by 325 nm micro-Raman spectroscopy, x-ray photoelectron spectroscopy (XPS), reflective second harmonic generation (RSHG), and synchrotron x-ray diffraction (XRD). Optical inspection was integrated into these processes to establish a multi-optical method. 325 nm micro-Raman spectroscopy was used to determine variations in Si-Si, Si-Ge, and Ge-Ge bonds in BSG. XPS exhibited the binding energy evolution of Ge3d during different annealing processes at varied Ge ratios and B concentrations. RSHG revealed the polar Si-B and Ge-B bonds formed during annealing. Synchrotron XRD provided the structure and strain changes of BSG. Secondary-ion mass spectrometer profiles provided the species distribution, which was used to examine the results of multi-optical method. Furthermore, double-layered BSG (DBSG) with different B concentrations were analyzed using the multi-optical method. Results revealed that Ge aggregated in the homogeneous interface of DBSG, and that B dopants in BSG served as carrier providers that strongly influenced the BSG structure. However, BSG with excessive B concentration was unstable and increased the B content (SiB3) through metallization. For BSG with a suitable B concentration, the formation of Si-B and Ge-B bonds suppressed the diffusion of Ge from SiGe, thereby reducing the possibility of Ge loss and further B pipe-up in the heavily doped S/D region.

Differentiation and Characterization of Excitatory and Inhibitory Synapses by Cryo-electron Tomography and Correlative Microscopy.

As key functional units in neural circuits, different types of neuronal synapses play distinct roles in brain information processing, learning, and memory. Synaptic abnormalities are believed to underlie various neurological and psychiatric disorders. Here, by combining cryo-electron tomography and cryo-correlative light and electron microscopy, we distinguished intact excitatory and inhibitory synapses of cultured hippocampal neurons, and visualized the in situ 3D organization of synaptic organelles and macromolecules in their native state. Quantitative analyses of >100 synaptic tomograms reveal that excitatory synapses contain a mesh-like postsynaptic density (PSD) with thickness ranging from 20 to 50 nm. In contrast, the PSD in inhibitory synapses assumes a thin sheet-like structure ∼12 nm from the postsynaptic membrane. On the presynaptic side, spherical synaptic vesicles (SVs) of 25-60 nm diameter and discus-shaped ellipsoidal SVs of various sizes coexist in both synaptic types, with more ellipsoidal ones in inhibitory synapses. High-resolution tomograms obtained using a Volta phase plate and electron filtering and counting reveal glutamate receptor-like and GABAA receptor-like structures that interact with putative scaffolding and adhesion molecules, reflecting details of receptor anchoring and PSD organization. These results provide an updated view of the ultrastructure of excitatory and inhibitory synapses, and demonstrate the potential of our approach to gain insight into the organizational principles of cellular architecture underlying distinct synaptic functions.SIGNIFICANCE STATEMENT To understand functional properties of neuronal synapses, it is desirable to analyze their structure at molecular resolution. We have developed an integrative approach combining cryo-electron tomography and correlative fluorescence microscopy to visualize 3D ultrastructural features of intact excitatory and inhibitory synapses in their native state. Our approach shows that inhibitory synapses contain uniform thin sheet-like postsynaptic densities (PSDs), while excitatory synapses contain previously known mesh-like PSDs. We discovered "discus-shaped" ellipsoidal synaptic vesicles, and their distributions along with regular spherical vesicles in synaptic types are characterized. High-resolution tomograms further allowed identification of putative neurotransmitter receptors and their heterogeneous interaction with synaptic scaffolding proteins. The specificity and resolution of our approach enables precise in situ analysis of ultrastructural organization underlying distinct synaptic functions.