The Impact of potential 'confounders' on the diagnostic sensitivity of circulating free DNA in management of FIT+ patients: a pilot study.

Cell-free DNA (cfDNA) has long been established as a useful diagnostic and prognostic tool in a variety of clinical settings, ranging from infectious to cardiovascular and neoplastic diseases. However, non-neoplastic diseases can act as confounders impacting on the amount of cfDNA shed in bloodstream and on technical feasibility of tumour derived free circulating nucleic acids selecting patients with cancer. Here, we investigated the potential impact of other pathological processes in the clinical stratification of 637 FIT+ patients. A single and multiple logistic regression yielded similar results. Crude sensitivity was 75.9% versus adjusted sensitivity of 74.1%, relative risk 0.9761 (0.8516 to 1.1188), risk difference 0.0181 (-0.0835 to 0.1199) and OR 0.9079 (0.5264 to 1.5658). Potential confounding effect from other source of cfDNA plays a pivotal role in the clinical stratification of FIT+ patients.

TONSL Is an Immortalizing Oncogene and a Therapeutic Target in Breast Cancer.

Study of genomic aberrations leading to immortalization of epithelial cells has been technically challenging due to the lack of isogenic models. To address this, we used healthy primary breast luminal epithelial cells of different genetic ancestry and their hTERT-immortalized counterparts to identify transcriptomic changes associated with immortalization. Elevated expression of TONSL (Tonsoku-like, DNA repair protein) was identified as one of the earliest events during immortalization. TONSL, which is located on chromosome 8q24.3, was found to be amplified in approximately 20% of breast cancers. TONSL alone immortalized primary breast epithelial cells and increased telomerase activity, but overexpression was insufficient for neoplastic transformation. However, TONSL-immortalized primary cells overexpressing defined oncogenes generated estrogen receptor-positive adenocarcinomas in mice. Analysis of a breast tumor microarray with approximately 600 tumors revealed poor overall and progression-free survival of patients with TONSL-overexpressing tumors. TONSL increased chromatin accessibility to pro-oncogenic transcription factors, including NF-κB and limited access to the tumor-suppressor p53. TONSL overexpression resulted in significant changes in the expression of genes associated with DNA repair hubs, including upregulation of several genes in the homologous recombination (HR) and Fanconi anemia pathways. Consistent with these results, TONSL-overexpressing primary cells exhibited upregulated DNA repair via HR. Moreover, TONSL was essential for growth of TONSL-amplified breast cancer cell lines in vivo, and these cells were sensitive to TONSL-FACT complex inhibitor CBL0137. Together, these findings identify TONSL as a regulator of epithelial cell immortalization to facilitate cancer initiation and as a target for breast cancer therapy. SIGNIFICANCE: The chr.8q24.3 amplicon-resident gene TONSL is upregulated during the initial steps of tumorigenesis to support neoplastic transformation by increasing DNA repair and represents a potential therapeutic target for treating breast cancer.

Racial Differences in Cumulative Disadvantage Among Women and Its Relation to Health: Development and Preliminary Validation of the Cumulative Stress Inventory of Women's Experiences.

Background: Cumulative disadvantage (CD) is a measure of accumulated social, economic, and person-related stressors due to unequal access to resources and opportunities, which increases a person's biological risk for disease. The purpose of this research was to develop an instrument tailored to women's experiences that had intervention and translational potential. In addition, we explored whether CD contributed to racial health disparities among black and white women. Methods: In-depth life course interviews were used to assess stressful experiences of 15 black and 15 white women. Using information from the interviews, we developed the Cumulative Stress Inventory of Women's Experiences (CSI-WE) as a quantitative instrument to measure stressful life experiences from childhood to adulthood. The CSI-WE was then administered to the original 30 women for validation and feedback. Results: Qualitative and quantitative assessments were highly correlated, which suggested that the CSI-WE reliably captured the experiences of the interviewed women. Black participants reported significantly higher numbers of childhood and adult stressors, more acute adulthood and lifetime stressors, and worse adult physical self-rated health. Conclusions: This study supports the preliminary validity of an instrument that once fully validated may be used in future studies to elucidate the experiences of CD among black and white women and examines how these experiences relate to perceived and objective health status.

An MgB2 Superconducting Joint with its Own Heat-Treatment Schedule.

We suggested an MgB2 joint process with its own heat-treatment schedule to apply it for our 1.5-T MgB2 "finger" MRI magnet. In fabricating the MgB2 magnet, the optimal heat-treatment schedule to attain a reproducible and high critical current is different in a joint and a coil. To solve this problem, we introduced an additional heating system, which is composed of a cartridge heater and a thermocouple connected with a copper block, into a box-type furnace. Then, we carried out heat-treatments with exclusively increasing the joint-part temperature above the Mg melting point of 645 °C-the joint was actually heated up to 700 °C. We evaluated a critical current and a crystal structure of the obtained MgB2 joint. From experimental results, we found that the joint heated with the own heat-treatment schedule, which is 700 °C for 1 h + 600 °C for 11 h, showed a good I c of over 450 A at 15K under self-field. The joint resistance was estimated by the coil operation for 18 days, and it was expected to be less than 10-12 Ω.

Pilot Study on Neonatal Screening for Methylmalonic Acidemia Caused by Defects in the Adenosylcobalamin Synthesis Pathway and Homocystinuria Caused by Defects in Homocysteine Remethylation.

Neonatal screening (NS) for methylmalonic acidemia uses propionylcarnitine (C3) as a primary index, which is insufficiently sensitive at detecting methylmalonic acidemia caused by defects in the adenosylcobalamin synthesis pathway. Moreover, homocystinuria from cystathionine ß-synthase deficiency is screened by detecting hypermethioninemia, but methionine levels decrease in homocystinuria caused by defects in homocysteine remethylation. To establish NS detection of methylmalonic acidemia and homocystinuria of these subtypes, we evaluated the utility of indices (1) C3 ≥ 3.6 µmol/L and C3/acetylcarnitine (C2) ≥ 0.23, (2) C3/methionine ≥ 0.25, and (3) methionine < 10 µmol/L, by retrospectively applying them to NS data of 59,207 newborns. We found positive results in 116 subjects for index (1), 37 for (2), and 15 for (3). Second-tier tests revealed that for index 1, methylmalonate (MMA) was elevated in two cases, and MMA and total homocysteine (tHcy) were elevated in two cases; for index 2 that MMA was elevated in one case; and for index 3 that tHcy was elevated in one case. Though data were anonymized, two cases identified by index 1 had been diagnosed with maternal vitamin B12 deficiency during NS. Methylene tetrahydrofolate reductase deficiency was confirmed for the case identified by index 3, which was examined because an elder sibling was affected by the same disease. Based on these data, a prospective NS study is underway.

Aging- and Tumor-Mediated Increase in CD8+CD28- T Cells Might Impose a Strong Barrier to Success of Immunotherapy in Glioblastoma.

Clinical use of various forms of immunotherapeutic drugs in glioblastoma (GBM), has highlighted severe T cell dysfunction such as exhaustion in GBM patients. However, reversing T cell exhaustion using immune checkpoint inhibitors in GBM clinical trials has not shown significant overall survival benefit. Phenotypically, CD8+ T cells with downregulated CD28 coreceptors, low CD27 expression, increased CD57 expression, and telomere shortening are classified as senescent T cells. These senescent T cells are normally seen as part of aging and also in many forms of solid cancers. Absence of CD28 on T cells leads to several functional irregularities including reduced TCR diversity, incomplete activation of T cells, and defects in Ag-induced proliferation. In the context of GBM, presence and/or function of these CD8+CD28- T cells is unknown. In this clinical correlative study, we investigated the effect of aging as well as tumor microenvironment on CD8+ T cell phenotype as an indicator of its function in GBM patients. We systematically analyzed and describe a large population of CD8+CD28- T cells in both the blood and tumor-infiltrating lymphocytes of GBM patients. We found that phenotypically these CD8+CD28- T cells represent a distinct population compared with exhausted T cells. Comparative transcriptomic and pathway analysis of CD8+CD28- T cell populations in GBM patients revealed that tumor microenvironment might be influencing several immune related pathways and thus further exaggerating the age associated immune dysfunction in this patient population.

Crystal Growth and High-Pressure Effects of Bi-Based Superconducting Whiskers.

Three growth methods were tested for producing high-transition temperature superconducting Bi2Sr2Ca n-1Cu n O2n+4+δ whiskers, employing different ways to focus a compressive stress and size effect of the precursors. First, thermographic imaging was used to investigate thermal stress from temperature distribution in the precursors during growth annealing. To enhance thermal stress in the precursors, a thermal cycling method and a Ag-paste coating method were proposed and found to significantly accelerate the whisker growth. The use of pulverized precursors also promoted whisker growth, possibly due to contribution from the vapor-liquid-solid growth mechanism. The obtained whiskers revealed the typical composition, diffraction patterns, and superconducting properties of the Bi-2212 phase. The proposed methods were able to stably produce longer whiskers compared to the conventional method. Using the obtained whiskers, electrical transport measurements under high pressure were successfully performed up to around 50 GPa.

EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.

BACKGROUND: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. METHODS: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. RESULTS: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated ß-galactosidase (SA-ß-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. CONCLUSIONS: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

In vitro blood compatibility evaluation method: incubating while rotating hemodialyzers filled with fresh human blood.

One of the often-used methods for in vitro evaluation of the blood compatibility of hemodialysis membranes is the circulation of human blood through a miniaturized hemodialyzer. The use of a rather small amount of human blood in its evaluation is one advantage of this method. However, because it is manufactured by a different process than actual ones, a miniaturized hemodialyzer membrane cannot always preserve the properties of actual hemodialyzers. To address this problem, we established a new experimental method that uses a relatively small amount of human blood and actual dialyzers. In this method, a test hemodialyzer and a control hemodialyzer filled with human blood obtained from the same donor is slowly rotated to prevent spontaneous blood cell sedimentation for 4 h at 37 °C. By use of this method, we were able to compare blood compatibility between a polysulfone (PS) membrane and a vitamin E (VE)-bonded PS membrane in terms of their relative antithrombotic, antioxidative, and anti-inflammatory properties. Consistent with many previous reports, the results clearly showed that compared with the PS membrane, VE-bonded PS membrane is more blood compatible. These findings suggest that our method is applicable, at least to in vitro blood compatibility evaluation of PS type dialysis membranes.

Crystal Growth, Structural Analysis, and Pressure-Induced Superconductivity in a AgIn5Se8 Single Crystal Explored by a Data-Driven Approach.

A high-throughput first-principles calculation-assisted data-driven approach based on an inorganic materials database named AtomWork was performed to explore new superconducting materials. Specific band structures of a small band gap and flat band at band edges were used in a screening procedure. Among the candidates studied, we focused on AgIn5Se8, which shows a high density of state at the Fermi level. Single crystals of AgIn5Se8 were successfully obtained via a melt and slow cooling method. The valence states in AgIn5Se8 were estimated to be Ag1+, In3+, and Se2- using X-ray photoelectron spectroscopy. An electrical transport property of resistance was measured under high pressure using an electrodes-inserted diamond anvil cell. The sample exhibited an insulator-to-metal transition with a drastic decrease of the resistance by increasing the pressure up to 24.8 GPa. A possibility of a pressure-driven phase transition below this pressure was indicated by an enthalpy calculation. At a higher pressure region of 52.5 GPa, a pressure-induced superconducting transition was observed at 3.4 K. The maximum transition temperature was increased up to 3.7 K under the pressure of 74.0 GPa.

The Role and Therapeutic Potential of miRNAs in Colorectal Liver Metastasis.

Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. Liver metastasis is the major cause of CRC patient mortality, occurring in 60% patients with no effective therapies. Although studies have indicated the role of miRNAs in CRC, an in-depth miRNA expression analysis is essential to identify clinically relevant miRNAs and understand their potential in targeting liver metastasis. Here we analyzed miRNA expressions in 405 patient tumors from publicly available colorectal cancer genome sequencing project database. Our analyses showed miR-132, miR-378f, miR-605 and miR-1976 to be the most significantly downregulated miRNAs in primary and CRC liver metastatic tissues, and CRC cell lines. Observations in CRC cell lines indicated that ectopic expressions of miR-378f, -605 and -1976 suppress CRC cell proliferation, anchorage independent growth, metastatic potential, and enhance apoptosis. Consistently, CRC patients with higher miR-378f and miR-1976 levels exhibited better survival. Together, our data suggests an anti-tumorigenic role of these miRNAs in CRC and warrant future in vivo evaluation of the molecules for developing biomarkers or novel therapeutic strategies.

Author Correction: Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Did kindergarteners who experienced the Great East Japan earthquake as infants develop traumatic symptoms? Series of questionnaire-based cross-sectional surveys: A concise and informative title: traumatic symptoms of kindergarteners who experienced disasters as infants.

BACKGROUND: The Great East Japan Earthquake (GEJE) and tsunami of March 11, 2011 left behind many survivors, including children. This study aimed to assess changes in traumatic symptoms with time among kindergarteners who experienced GEJE as infants and to discuss the relationship between these symptoms and the disaster experience. METHODS: The 15-item Post-Traumatic Stress Symptoms for Children (PTSSC-15) questionnaire were distributed to the parents of kindergarteners (children aged 4-5 years) at 8, 20, 30, and 42 months after GEJE. Questionnaires regarding environmental damage conditions affecting the children were distributed to teachers 8 months after the tsunami. RESULTS: The number of kindergarteners was 262, 255, 236, and 202 at 8, 20, 30, and 42 months after the disaster. The PTSSC-15 total score was not different between kindergartners with and without environmental damage conditions. After 8 and 20 months, the PTSSC-15 total score of children who usually ate breakfast was significantly higher than that of children who did not. Moreover, after 30 and 42 months, the PTSSC-15 total score of kindergarteners who usually ate breakfast was not significantly higher than that of kindergarteners who did not. CONCLUSIONS: The traumatic symptoms of kindergarteners were not related to disaster experiences.

Efficient Generation of Pancreas/Duodenum Homeobox Protein 1+ Posterior Foregut/Pancreatic Progenitors from hPSCs in Adhesion Cultures.

Human pluripotent stem cell (hPSC)-derived pancreatic cells are a promising cell source for regenerative medicine and a platform to study human developmental processes. Stepwise directed differentiation that recapitulates developmental processes is one of the major ways to generate pancreatic cells including pancreas/duodenum homeobox protein 1+ (PDX1+) pancreatic progenitor cells. Conventional protocols initiate the differentiation with small colonies shortly after the passage. However, in the state of colonies or aggregates, cells are prone to heterogeneities, which might hamper the differentiation to PDX1+ cells. Here, we present a detailed protocol to differentiate hPSCs into PDX1+ cells. The protocol consists of four steps and initiates the differentiation by seeding dissociated single cells. The induction of SOX17+ definitive endoderm cells was followed by the expression of two primitive gut tube markers, HNF1ß and HNF4α, and eventual differentiation into PDX1+ cells. The present protocol provides easy handling and may improve and stabilize the differentiation efficiency of some hPSC lines that were previously found to differentiate inefficiently into endodermal lineages or PDX1+ cells.

Advanced microscopic evaluation of parallel type I and type II cell deaths induced by multi-functionalized gold nanocages in breast cancer.

Despite aggressive surgical resections and combinatorial chemoradiations, certain highly malignant populations of tumor cells resurrect and metastasize. Mixed-grade cancer cells fail to respond to standard-of-care therapies by developing intrinsic chemoresistance and subsequently result in tumor relapse. Macroautophagy is a membrane trafficking process that underlies drug resistance and tumorigenesis in most breast cancers. Manipulating cellular homeostasis by a combinatorial nanotherapeutic model, one can evaluate the crosstalk between type I and type II cell death and decipher the fate of cancer therapy. Here, we present a multi-strategic approach in cancer targeting to mitigate the autophagic flux with subcellular toxicity via lysosome permeation, accompanied by mitochondrial perturbation and apoptosis. In this way, a nanoformulation is developed with a unique blend of a lysosomotropic agent, an immunomodulating sulfated-polysaccharide, an adjuvant chemotherapeutic agent, and a monoclonal antibody as a broad-spectrum complex for combinatorial nanotherapy of all breast cancers. To the best of our knowledge, this manuscript illustrates for the first time the applications of advanced microscopic techniques such as electron tomography, three-dimensional rendering and segmentation of subcellular interactions, and fate of the multifunctional therapeutic gold nanocages specifically targeted toward breast cancer cells.

Behavioral, hormonal, and neurochemical outcomes of neonatal repeated shaking brain injury in male adult rats.

It is well known that an abusive environment in childhood is related to individual anxiety behavior in adulthood. Though an imbalance of adrenocorticosteroid receptors and a dysfunction of monoaminergic neuron systems have been proposed, the underlying mechanisms are not fully understood. To address these problems, we recently developed a new model of shaking brain injury (SBI) in neonatal rats. These model rats showed transient microhemorrhages in the gray matter of the cerebral cortex and hippocampus. Using this model, we assessed the effects of neonatal repeated mild SBI on subsequent behavior and the stress response, and we further examined the possible contribution of adrenocorticosteroid receptors in the hippocampus and central monoaminergic neuron systems mediating such abnormalities. Behavioral screening examination with a novel open-field test showed that the rats with postnatal day (P) 3-7 shaking had significantly reduced locomotor activity and exploration behaviors than those with late (P8-14) shaking periods, indicating a critical period for neonatal SBI. In the elevated plus maze (EPM) and the light/dark transition (L/D) tests, the model rats spent less time in the open arm of the EPM and the light box of the L/D test, indicating anxiety-like behavior as adults. In adults, the novel EPM-induced adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) responses were significantly increased by neonatal SBI. Further experiments showed that the expression of mineralocorticoid receptor (MR), but not glucocorticoid receptor (GR), was significantly downregulated in the hippocampus of this model rat. These results suggest that neonatal SBI-induced downregulation of MRs in the hippocampus attenuates negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which results in abnormal secretion of ACTH and CORT. Furthermore, the neurochemical analysis showed that shaken rats had higher dopamine (DA), serotonin (5-HT), 5-hydroxyindolacetic acid (5-HIAA), and noradrenaline (NA) levels in the dorsal part of the medial prefrontal cortex (dmPFC). In the amygdala, higher 5-HIAA and lower NA levels were observed. Both areas are known to be anxiety and stress-related. Taken together, the effects of neonatal SBI on the monoaminergic systems may also be involved in the changes of behavioral and hormonal responses in this model.

Development of new method to enrich human iPSC-derived renal progenitors using cell surface markers.

Cell therapy using renal progenitors differentiated from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) has the potential to significantly reduce the number of patients receiving dialysis therapy. However, the differentiation cultures may contain undifferentiated or undesired cell types that cause unwanted side effects, such as neoplastic formation, when transplanted into a body. Moreover, the hESCs/iPSCs are often genetically modified in order to isolate the derived renal progenitors, hampering clinical applications. To establish an isolation method for renal progenitors induced from hESCs/iPSCs without genetic modifications, we screened antibodies against cell surface markers. We identified the combination of four markers, CD9-CD140a+CD140b+CD271+, which could enrich OSR1+SIX2+ renal progenitors. Furthermore, these isolated cells ameliorated renal injury in an acute kidney injury (AKI) mouse model when used for cell therapy. These cells could contribute to the development of hiPSC-based cell therapy and disease modeling against kidney diseases.

Development of a New Monochrome Multiplex qPCR Method for Relative Telomere Length Measurement in Cancer.

Excess telomere shortening has been observed in most cancer cells. The telomere quantitative polymerase chain reaction (qPCR) assay has become an important tool for epidemiological studies examining the effects of aging, stress, and other factors on the length of telomeres. Current telomere qPCR methods analyze the relative length of telomeres by amplifying telomere sequence products and normalizing with single-copy gene products. However, the current telomere qPCR does not always reflect absolute telomere length in cancer DNA. Because of genomic instability in cancer cells, we hypothesized that the use of single-copy genes (scg) is less accurate for normalizing data in cancer DNA and that new primer sets are required to better represent relative telomere length in cancer DNA. We first confirmed that cancer cells had a different copy ratio among different scg, implying that DNA is aneuploid. By using the new primer sets that amplify multiple-copy sequences (mcs) throughout the genome, the telomere qPCR results showed that the mcs primers were interchangeable with the scg primers as reference primers in normal DNA. By comparing results from the traditional southern blotting method (as kilobases) and results from monochrome multiplex qPCR using the mcs primers (as T/M ratios), we verified that the T/M ratio is highly correlated with absolute telomere length from the southern blot analysis. Together, the mcs primers were able to represent the telomere lengths accurately in cancer DNA samples. These results would allow for analyses of telomeres within cancerous DNA and the development of new, less invasive diagnostic tools for cancer.

A plasma telomeric cell-free DNA level in unaffected women with BRCA1 or/and BRCA2 mutations: a pilot study.

Plasma cell-free DNA (cfDNA) is a small DNA fragment circulating in the bloodstream originating from both non-tumor- and tumor-derived cells. A previous study showed that a plasma telomeric cfDNA level decreases in sporadic breast cancer patients compared to controls. Tumor suppressor gene products including BRCA1 and BRCA2 (BRCA1&2) play an important role in telomere maintenance. In this study, we hypothesized that the plasma telomeric cfDNA level is associated with the mutation status of BRCA1&2 genes. To test this hypothesis, we performed plasma telomeric cfDNA quantitative PCR (qPCR)-based assays to compare 28 women carriers of the BRCA1&2 mutation with age-matched controls of 28 healthy women. The results showed that the plasma telomeric cfDNA level was lower in unaffected BRCA1&2 mutation carriers than in age-matched controls from non-obese women (BMI < 30), while there was no association between unaffected BRCA1&2 mutation carriers and age-matched controls in obese women (BMI > 30). Moreover, the plasma telomeric cfDNA level applied aptly to the Tyrer-Cuzick model in non-obese women. These findings suggest that circulating cfDNA may detect dysfunctional telomeres derived from cells with BRCA1&2 mutations and, therefore, its level is associated with breast cancer susceptibility. This pilot study warrants further investigation to elucidate the implication of plasma telomeric cfDNA levels in relation to cancer and obesity.

Retreat from Stress: Rattling in a Planar Coordination.

Thermoelectric devices convert heat flow to charge flow, providing electricity. Materials for highly efficient devices must satisfy conflicting requirements of high electrical conductivity and low thermal conductivity. Thermal conductivity in caged compounds is known to be suppressed by a large vibration of guest atoms, so-called rattling, which effectively scatters phonons. Here, the crystal structure and phonon dynamics of tetrahedrites (Cu,Zn)12 (Sb,As)4 S13 are studied. The results reveal that the Cu atoms in a planar coordination are rattling. In contrast to caged compounds, chemical pressure enlarges the amplitude of the rattling vibration in the tetrahedrites so that the rattling atom is squeezed out of the planar coordination. Furthermore, the rattling vibration shakes neighbors through lone pairs of the metalloids, Sb and As, which is responsible for the low thermal conductivity of tetrahedrites. These findings provide a new strategy for the development of highly efficient thermoelectric materials with planar coordination.